The subject matter of the invention is a method of preparing phthalide by the chlorination of o-toluic acid at elevated tempreatures and processing the chlorination mixture to phthalide, wherein, if any o-chloromethyl benzoic acid or o-dichloromethylbenzoic acid is present it is cyclized to phthalide or 3-chlorophthalide, and if there is any 3-chlorophthalide present it is hydrogenated to phthalide.
Phthalide, which is also known as 1-(3H)-isobenzofuranone, is known, and it is desired as an intermediate for pharmaceutical chemistry, for example for the synthesis of bromophthalide which is required for penicillin and cephalosporin derivatives. Phthalide is also used directly as an anthelmintic. Phthalide is also useful for the synthesis of anthraquinone dyes.
A number of methods of preparation have been described (Beilstein, System No. 2463, vol. 17, p. 310, Erg. Bd. 17 I, p. 161, II, p. 332, III & IV, p. 4948). Many authors set out from o-xylols polysubstituted with oxygen or halogen, e.g., from phthalic aldehyde, phthalyl alcohol, .alpha.-di- to tetrachlorozylenes, but also 2-cyanobenzyl halide among others. Toluic acid derivatives can be hydrolyzed oxidatively to phthalide, using lead or copper nitrate solutions, chromic acid, nitric acid, potassium persulfate, and the like as oxidants; hydrolyses often have to be performed at 200.degree. C. under pressure.
Disadvantages of these methods are the expensive starting materials, the usually insufficient purity of the phthalide, the necessity of stoichiometric amounts of the oxidants, and the production of large amounts of solutions of the used oxidants.
Other investigators have produced phthalide from phthalic acid anhydride by reduction, for example with zinc dust in hydrochloric acid or acetic acid, and also with LiAlH.sub.4, sodium boranate, sodium amalgam, or with a mixture of hydrogen iodide and yellow phosphorus. In the reduction with zinc dust in acetic acid, undesirable by-products are formed, such as diphthalyl, hydrodiphthalyl and .alpha.-(phthalidyl-3)-o-toluic acid, plus the undesirable ZnCl.sub.2. The other reductants are expensive laboratory chemicals and are difficult to handle. In technical processes they would be uneconomical.
Catalytic hydrogenations of phthalic acid anhydride (PAA) are performed at high temperatures of 150.degree. to 600.degree. C. and high pressures of 85 to 300 atmospheres, using catalysts such as nickel, platinum, aluminum, or copper chromic oxide. These pressure hydrogenations call for complex apparatus and give unclean products in unsatisfactory yields, sometimes containing dissolved catalysts.
In the electrochemical reduction of German Auslegeschrift 21 44 419, phthalic acid anhydride is first transformed to ammonium phthalamate, a solution of which (in a mixture of water and organic solvent) is reduced on a lead cathode. This process requires a complex apparatus, special knowledge and costly electrically power.
Other methods which can be used only in the laboratory produce phthalide by reduction from phthalimide or from N-nitrosophthalimidine (Houben-Weyl O/2, pp. 735-736).
In a brief report containing no information on yeild, E. Hjelt, in Ber. 19 (1886) 412, describes the bromination of o-toluic acid to phthalide at 140.degree. C. When its reproduction was attempted it was found that at no time is phthalide present in concentrations of more than 20%, and accordingly it is transformed preferentially, further, to bromophthalide. Due to the large amounts of the by-products, toluic acid, bromophthalide, 3-(o-carboxybenzyl)-phthalide and others, phthalide is obtained only with difficulty and in very low yields, and it is furthermore heavily contaminated, especially by hard-to-remove substances which are formed by the oxidative action of bromine.